Canine mast cell disease: introducing tyrosine-kinase inhibitors to their treatment plan (Proceedings)

Mast cell tumors are the most commonly encountered malignant skin tumor in the dog. They account for 16-21% of all cutaneous tumors and boxers, Boston terriers, Labrador retrievers, beagles and schnauzers are documented to be at increased risk. Alterations in the c-kit receptor (receptor for growth factor SCF) are noted in many high grade tumors. Histologic grade is highly predictive of behavior.

Paraneoplastic conditions noted in conjunction with mast cell disease include gastrointestinal ulceration secondary to increased circulating histamine levels, coagulation abnormalities secondary to heparin levels, and delayed wound healing secondary to fibroblast suppressor factor released by macrophages recruited by tumor cells.

The clinical appearance of mast cell tumors is extremely variable and this is why every dermal mass, almost without exception, should be aspirated. Fine needle aspiration cytology is usually sufficient to diagnose a mast cell tumor. The grade of the tumor cannot be reliably determined without histopathology.

Once a mast cell tumor is identified, the regional lymph node should be aspirated if possible. A CBC, biochemical profile and urinalysis are recommended to assess the patient's physiologic status. Abdominal radiographs, abdominal ultrasound, and bone marrow aspirates can also be considered to complete staging. Buffy coat smears are felt to be unreliable in most cases.

Aggressive surgical resection is the treatment of choice. Pre-surgical imaging of the tumor with a CT or MRI may be indicated to help plan adequate excision. Always submit the sample for histopathologic analysis. The prognosis and indication for adjuvant chemotherapy will be dictated by the histologic grade. Evaluation of the margins will also affect prognosis and the indication for adjuvant radiation therapy.

Grade I mast cell tumors usually do not require further therapy as over 90% of those patients will die from other causes. The more difficult decision is the grade II patient with a marginal resection (margins <5-10 mm). We know that at least 50% of those cases should be fine without further intervention based on the early studies where surgery was the only modality applied. We can increase the number to ~90% with the addition of radiation therapy. These findings would indicate there are roughly 1/3 of cases in which the radiation therapy is highly indicated. It is not often possible to identify which of the animals that meet the description above will recur and which won't. Recurrence is a negative prognostic variable so the owner must know that if they wish to be conservative, their prognosis will be more guarded should recurrence occur. Chemotherapy may also delay the onset of recurrence.

Grade III mast cell tumors, high grade II tumors with marginal resections, or those with positive lymph nodes, should consider adding chemotherapy to their treatment regimen. Vinblastine, prednisone and CCNU have all demonstrated moderate activity in canine mast cell disease. Recently toceranib (Palladia) and masitinib were added to the list of single agents with activity. Reported single agent response rates in the setting of gross disease have been 12-27% for vinblastine, 42% for CCNU, 55% for masitinib and 43% for toceranib. Response rates improve to the 47-63% range when prednisone is added to vinblastine or CCNU. Given the significant activity of toceranib and masitinib as a single agent, combination protocols would also be expected to increase response rates in these drugs.

The interest in tyrosine kinase inhibitors was greatly heightened following the success of imitinab (Gleevec) in the treatment of human chronic myelogenous leukemia and gastrointestinal stromal tumors. This compound will inhibit KIT, abl and PDGFR. Understanding that KIT is critical for the development and growth of canine mast cells, and that the prevalence of KIT mutations is ~25% in grade 2 and 3 canine mast cell tumors, led to the clinical development of toceranib and masitinib in the veterinary setting. Strong responses can also be noted in animals that don't have KIT mutations indicating that other mechanisms of actions must also be present. Evidence in toceranib indicates this activity is strongly related to its antiangiogenic effects via VEGFR and PDGFR inhibition. There is also preliminary evidence that these compounds are effective radiosensitizers. As you can tell, we've only scratched the surface of how best to use these compounds.

All kinase inhibitors have potential toxicities. In general the more receptors they inhibit, the more potential for toxicity. Gastrointestinal side effects are the most common dose limiting toxicity. It is very important to treat these early and aggressively. It is currently recommended that patients are rechecked at weekly intervals in the beginning of their treatment as dose modifications and concominant medications are almost always required. Life threatening toxicities are rare, and early recognition of potential problems is critical.

Because of the high circulating levels of histamine associated with mast cell disease, these patients are already predisposed to gastrointestinal ulceration, which is also a potential side effect of these drugs. Any patient with bulky disease present should be on a preventative H2 or proton pump inhibitor. Sucralfate may also be added. Antidiarrheals are also often required. Loperamide appears to benefit most patients and may need to be taken frequently throughout the clinical course. Pepto-bismol and metronidazole can also be effective. Anti-nausea agents such as maropitant, ondansetron and metoclopramide may also be helpful. Don't hesitate to give these patients a drug holiday, or decrease the dose, if they are starting to lose weight, having difficulty controlling the diarrhea or becoming anorexic.

Agent specific toxicities are also noted. Imitinab (Gleevec) can be hepatoxic. Neutropenia and muscle cramping have been associated with toceranib (Palladia) administration, and hypoalbuminemia and protein losing nephropathy with masitinib.

We recommend that these compounds be given with food.

The label dose of toceranib is 3.25 mg/kg every other day, and that of masitinib is 12.5 mg/kg daily. Because the spectrum of activity of masitinib is narrower, it may be better tolerated than the multi-targeted toceranib is some cases. It remains to be seen whether the two are equivalent in activity as head to head comparisons have not taken place. We do know though that resistance to one does not necessarily imply resistance to the other. There is now good evidence that at least for toceranib significant activity can be seen at doses as low as 2.5 mg/kg.

Expect to see much more data regarding tyrosine kinase inhibitors as part of a multi-drug treatment regimen in the near future. It does appear that prednisone can be added to the off days of toceranib as long as one monitors the patient carefully. Expect to see it added to palliative radiation therapy protocols as well.

How long to administer these compounds is a difficult question. In the human realm they are most often given until they don't work anymore. At the present time we've recommend at least six months of administration if at all possible.

It is exciting to have new drugs with significant activity in canine mast cell disease. More work is required to understand how to maximize their impact on the disease, but it is hopeful that their incorporation into the treatment plan will result in increased progression free survival times, and survival times, while allowing the patients to enjoy a good to excellent quality of life.